Method of suppressing reproduction with substituted cyclic carboxylic acids and esters

ABSTRACT

Phenyl-cyclohexenecarboxylic acids having a substituent on the phenyl ring and their alkali metal salts are described. The phenyl-cyclohexenecarboxylic acids are useful in the suppression of reproduction.

United States Patent 1191 Karmas 1451 Sept. 2, 1975 METHOD OFSUPPRESSING REPRODUCTION WITH SUBSTITUTED CYCLIC CARBOXYLIC ACIDS ANDESTERS [75] Inventor:

[73] Assignee: Ortho Pharmaceutical Corporation,

Raritan, NJ.

[22] Filed: July 20, 1973 [21] Appl. No.: 381,204

Related U-S. Application Data [63] Continuation-impart of Scr. No.96,651, Dec. 9, I970, abandoned, which is a continuation-in-part of Ser.No. 723,614, April 23, 1968, abandoned.

George Karmas, Bound Brook, NJ.

424/311; 424/312; 424/317 51 1m. 01. A0ln 9/28; A6lk 27/00 58 Field ofSearch 424/283, 305, 308, 311,

Primary ExaminerAlbert T. Meyers Assistant Examiner-Dale R. OreAttorney, Agent, or Firm-Benjamin F. Lambert 5 7 ABSTRACTPhenyl-cyclohexenecarboxylic acids having a substituent on the phenylring and their alkali metal salts are described. Thephenyl-cyclohexenecarboxylic acids are useful in the suppression ofreproduction.

13 Claims, N0 Drawings METHOD OF SUPPRESSING REPRODUCTION WITHSUBSTITUTED CYCLIC CARBOXYLIC ACIDS AND ESTERS This application is acontinuation-in-part of application Scr. No. 96,65l filed Dec. 9, 1970,which in turn is a continuation-impart of application Scr. No. 723,614filed Apr. 23, 1968, and both are now abandoned.

The present invention relates to phenylcyclohexenecarboxylic acids andto their preparation. More particularly, the invention relates to phenylcyclohexenecarboxylic acids which are substituted on the phenyl ring andto their alkali-metal salts.

The compounds of the invention have the following formulae:

RI] RI! l R COR R I u 2 O 0 MgBr 0 RI II g I 1 I lo @OR' n u L|.

wherein R is hydrogen, lower acyl of from two to nine carbon atoms ortctrahydropyranyl, R is hydrogen or lower alkyl of from one to eightcarbon atoms, R" is lower alkyl of from one to eight carbon atoms, andR' is hydrogen or lower acyl of from two to nine carbon atoms.

The compounds of formula 1 are intermediates in the preparation of thecompounds of formulae 2, 3, and 4. The compounds of formulae 2, 3, and 4are useful as antilittering agents and as agents for the suppression ofreproduction when given postcoitally. In particular, it has been foundthat the compounds of formulae 2, 3, and 4 possess antilitteringactivity at a low dose level when administered orally.

US. Pat. No. 2,582,253 teaches a method of preparing2-methyl-3-ethyl-4-(p-anisyl)-3-and 4-cyclohexene-carboxylie acids. Thesynthetic route followed by the patent has been found to beunsatisfactory for the preparation of the compounds of formulae 3 and 4.

The novel compounds of this invention are prepared according to thefollowing reaction scheme:

The lactone of formula 1 exists in four forms. The form h d tion of thiscompound, by-products zire formed arbitrarily designated the C-lactoneis further reacted whi h arc""v'ir'tu'i1lly irremovahle if impuritiesare y as follows:

H (H. O COH III It is of utmost importance that the compound of forem.The dehydration of the compound of formula II! is mula Ill be obtainedin a purified form, since upon de- 40 carried out as follows:

OH O H0 3 011 BF 3 (C 24, l o

m n. '2 c 15 CH III IV.

C H CH B- Lac tone The A -isomer of the compound of formula IV isobtained as follows:

it is boiled under reflux for 20 minutes. Hydrolysis is performed byadding 500 ml. of saturated aqueous am- OH 8 H COH Ho COHp-toluenesulfonic B-Laetone c H (33 i...

2 3 in 0 11 CH hot acetic acid III. V.

Compounds of formulae IV and V are also obtained by the dehydration ofcompounds of the formula:

CH3C

C H CH3 followed by hydrolysis to the free phenols with hot aqueouspotassium bicarbonate.

The following examples illustrate the invention and are not to beconstrued as imposing any limitations thereon.

EXAMPLE I C-Lactone of 2-Methyl-3ethyl-4-hydroxy-4-(p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic Acid monium acetateat l5C., after which the organic phase is diluted with 400 ml. of ether,and the entire mixture is filtered to remove magnesium particles. Theorganic phase is separated and washed with a further ml. of ammoniumacetate solution, with water, and then with 300 ml. of 10% aqueouspotassium carbonate. After drying with anhydrous magnesium sulfate, thesolution of reaction products is concentrated under vacuum and theresidual oil is heated over a period of one hour to a temperature of C.under 0.02 mm. of pressure in order to remove volatile materials such asunreacted ketoester, phenol tetrahydropyranyl ether, and otherby-products. The glassy residue which is not volatile at l40/0.02 mm.and weighs 61 g. is a complex mixture of lactones and hydroxyesters.

Ten grams of the non-volatile reaction product is developed onto achromatographic column of neutral alu mina. Elution with benzene andbenzene-ether mixtures affords a total of 3-4 g. of oily mixed lactones,as characterized by infrared spectra showing no hydroxyl absorption andwith carbonyl absorption at 5.6 to 5.8;. Crystallization is induced inone or more of the eluate residues and seed crystals are removed. All ofthe elu ates are combined and recrystallized from hexane containing asmall amount of ether to afford a total of 1.5 g. of the C-lactonc of2-methyl-3-ethyl-4-hydroxy'4( ptetrahydropyranyloxyphenyl)-cyclohexanecarboxylic acid as white prisms. The melting point range is95l 15C. with only insignificant spectral differences between thevarious crops. The designation, C-lactone, is applied to distinguishthis product from three other theoretically possible isomers which mayresult from configurational variations of the methyl and ethyl groups.

Anal: Calcd. for C H O C, 73.22; H, 8.19. Found: C, 73.46; H, 8.14.

Akmax. (KBr): 5.70, 7.84, 7.97, 8.46, 8.98, 9.87, 10.32, 10.76, 11.40,ll.85/.L.

EXAMPLE 11 2-l\/lethyl3-ethyl-4-hydroxy-4-( ptetrahydrognyranyloxyphenyl)cyclohexanecarboxylic Acid A mixture of 50 g. of the non-volatilereaction product obtained in Example I, 30 g. of sodium hydroxide, 500ml. of methanol and 170 ml. of water is stirred and boiled under refluxfor 2 hours. After dilution with 400 ml. of water, the saponificationmixture is evaporated under vacuum to a volume of 400 ml. to removemethanol. A viscous oil of non-saponifiable material (7.8 g.) is removedfrom the alkaline concentrate by extraction with ether, and to theaqueous phase is added 250 ml. of methylene dichloride. This two-phasesystem is stirred and maintained at C. while cold 5% hydrochloric acidis added until the aqueous phase displays an acidic reaction to testpaper. The layers are separated and the aqueous phase is furtherextracted with two small portions of methylene dichloride. The combinedmethylene dichloride solutions are rapidly washed twice with aqueoussodium chloride, dried with anhydrous magnesium sulfate and immediatelyfiltered to remove drying agent. Concentration of the methylenedichloride solution under vacuum affords a residue of crystalline solidplus viscous oil. Trituration with 100 ml. of methylene dichloride andfiltration provides 12 g. of crystalline hydroxyacid. Concentration andprolonged chilling of the mother liquor affords 9.5 g. more of thismaterial. The total of 21.5 g. consists of a mixture of epimers at thetetrahydropyranyl ether portion of the molecule.

The 2-methyl-3 -ethyl-4-hydroxy-4-( p-tetrahydropyranyloxyphenyl)cyclohexaneearboxylic acid may be separated into itsindividual epimers by fractional crystallization between acetone andethyl acetate. Thereis thus'obtained an isomer, arbitrarily called 1,which melts at l84l 85C. after recrystallization from acetone, and anisomer called 11, which melts at 194195C. after recrystallization fromethyl acetate.

Anal: Calcd. for 0 ,11, 0 C, 69.58; H, 8.34. (1) Found: C, 68.99; H,8.52. (ll) Found: C, 68.81; H, 8.43.

Akmax. (IzKBr): 2.82, 5.90, 8.04, 8.30, 8.46, 8.84, 8.99, 9.60, 9.72,10.35, 10.82, 11.43, 11.98 1.

Akmax. (llzKBr): 290,588, 8.10, 8.28, 8.41, 9.00, 9.28, 9.70, 11.03,11.80, 11.89, 12.00;.t.

Each of these isomers yields the same phenolic hydroxyacid whendepyranylated with aqueous methanolie dilute acid according to theprocess of Example 111.

Saponification, according to this example, of the crystalline C-lactonedescribed in Example I affords the same hydroxyacid epimer mixture whichis described above as having been obtained from the non-volatile crudeGrignard reaction product.

EXAMPLE lll 2-Methyl-3-ethyl-4-hydroxy-4-(phydroxyphenyl)cyclohexanecarboxylic Acid A mixture of 13.8 g. of thetetrahydropyranyl hydroxyacid (crystalline epimer mixture) of Examplell, 350 ml. of methanol, 45 ml. of water and 2.0 ml. of 12.5 N.hydrochloric acid is stirred at 2()25C. for 40 minutes. Five ml. ofpyridine and 350 ml. of water are added to the resulting clear solutionand it is evaporated under vacuum to a volume of 300 ml. to removemethanol and dihydropyran. To the residue of water and viscous oil isadded 35 ml. of 4 N. hydrochloric acid and the mixture is cxtracted withtwo 200 ml. portions of ether. The combined ether solution is washedtwice with water, dried with anhydrous magnesium sulfate, and evaporatedunder vacuum to a viscous oil. The latter is dissolved in 40 ml. ofmethylene dichloride and this solution is stored at 0C. to afford 7.5 gvof crystalline2-methyl-3-ethyl-4-hydroxy-4-(phydroxyphenyl)cyclohexanccarboxylic acid,m.p. 219222C. Recrystallization from acetone plus methylene dichlorideaffords the phenolic hydroxyacid as dense white granules which melt at222224C.

As noted in Example 11, similar depyranylation of the individualepimers, I and Il, yields hydroxyacid identical with that justdescribed.

Anal: Calcd. for C A-1 0 C, 69.04; H, 7.97. Found: C, 68.46; H, 8.05.

Mtmax. (KBr): 2.78, 3.06, 5.86, 8.07, 8.29, 8.63, 9.11, 10.31, 10.98,11.58, 11.90, 12.0011.-

EXAMPLE IV 2-Methyl3-ethyl4-hydroxy4-( p-acetoxyphenyl)cyclohexanecarboxylic Acid To a solution of 6.0 g. of2-methyl-3-cthyl-4-hydroxy- 4-( p-hydroxyphenyl)cyclohexanecarboxylicacid (Example lll) in ml. of pyridine is added 15 ml. of aceticanhydride. The mixture is maintained at 25C. for 15 minutes and theacetylation mixture is then hydrolyzed in ice and water. The oilyproduct is extracted with two 75 ml. portions of ether. The combinedether solution is washed with cold 5% hydrochloric acid to removepyridine, and it is dried with anhydrous magnesium sulfate andevaporated to a tacky crystalline residue which is recrystallized fromacetone plus hexane to afford 5.6 g. of 2-methyl-3-ethyl-4hydroxy-4-(pacetoxyphenyl)cyclohexanecarboxylie acid as white prisms which melt at199201C.

Anal: Calcd. for C ,,H ,O C, 67.48; H, 7.55. Found: C, 67.39; H, 7.67.

)tkmax. (KBr): 2.79, 5.71, 5.89, 8.17, 8.30, 10.89, 1 1.7011,.

EXAMPLE V Anhydride of 2-Methyl-3-ethyl-4-hydroxy-4-( p-acetoxyphenyl)cyclohexaneearboxylic Acid 4 To a rapidly stirred suspension of 4.7 g.of Z-methyl- 3ethyl-4-hydroxy-4-( p-hydroxyphenyl )cyclohexanecarboxylicacid (Example 111) in 40 ml. of acetic anhydride is added 2 ml. ofpyridine. After 5 minutes at 25C., the resulting clear solution ispoured into an ice and water mixture and vigorous stirring is maintainedfor 10 minutes to effect hydrolysis of the excess acetic anhydride. Thewhite crystalline solid which is formed is filtered off, washed wellwith water on the filter funnel, and is dried under vacuum to afford 5.2g. of white prisms which melt at l051 10C. Recrystallization from ethergives a material which melts at l l2-1 14C.

The infrared spectrum identifies this as the carboxylic acid anhydrideof 2-mcthyl-3-ethyl-4-hydroxy-4- (p-acetoxyphenyl)-cyclohexanecarboxylicacid, mono acetic acid solvate Anal: Calcd. for C;,,,H ,O,,: C, 66.86;H, C, 66.96; H. 7.40

)\)\maxv (KBr): 2.83, 5.50, 5.77, 8.12. 8.37, 8.57, 9.22, 10.00, 10.21,10.89, 11.79, 12.42 1.

7.34. Found:

EXAMPLE Vl Methyl 2-Methy1-3-ethyl-4-hydroxy-4-(ptetrahydropyranyloxyphenyl )eyclohexanecarboxylate A mixture of 4.0 g.of crystalline C-lactone of 2- methyl-3-ethyl-4-hydroxy-4-(ptetrahydropyranyloxyphenyl )cyclohexanecarboxylic acid (Example 1), 2.0g. of sodium hydroxide. 20 ml. of methanol and 20 ml. of water isstirred and boiled under reflux for 1 hour to effect saponification ofthe lactone. The clear aqueous methanolic solution is diluted with 130ml. of dimethylformamide and is evaporated under vacuum to a volume of65 ml., thus removing all methanol and water. To the residualdimethylformamide solution is added 4.7 ml. of dimethyl sulfate and thismixture is shaken at 25C. for 10 minutes and is again evaporated undervacuum to remove most of the remaining dimethylformamide. The pastyresidue is shaken with ether plus water, the layers are separated, andthe ether solution is washed with cold 2% aqueous sodium hydroxide. Itis dried with anhydrous magnesium sulfate and evaporated to afford 4.7g. of white, crystalline methyl2-methyl-3-ethyl-4-hydroxy-4-(ptetrahydropyranyloxyphenyl)cyclohexanecarboxylate, of m.p. l20l27C.

Anal: Calcd. for C H O C, 70.18; H, 8.57. Found: C, 70.37; H, 8.51.

Altmax. (KBr): 2.83, 5.81, 8.03, 8.29, 8.47, 8.99, 9.60. 10.30, 10.81,11.42, 11.98;.t.

EXAMPLE Vll Methyl 2-Methyl-3-ethyl-4-hydroxy-4-( p-hydroxyphenyl)cyclohexanecarboxylate A mixture of 4.0 g. of methyl2-methyl-3-ethyl-4- hydroxy-4-( p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylate (Example V1), 20 ml. of methanol and 2 ml. ofwater containing four drops of 12.5 N. hydrochloric acid is stirred at25C. for 20 minutes. To the resulting clear solution is added 120 ml. ofwater and 1.0 ml. of pyridine and this mixture is extracted with three60 ml. portions of ether. The combined ether solution is washed withcold 2% hydrochloric acid, and then water, followed by aqueous potassiumbicarbonate. The ether solution is dried with anhydrous magnesiumsulfate. and is evaporated to afford 2.5 g. of methylZ-methyl-3-ethyl-4-hydroxy-4-( phydroxyphenyl)cyclohexanecarboxylate asan amorphous glass.

Anal: Calcd. for C, H- O,: C, 69.83; H, 8.28. Found: C. 69.28; H, 8.38.

xxmax. (Neat): 2.90, 5.82, 8.25. 8.58, 9.63. 9.82, 12.00a.

EXAMPLE Vlll Methyl 2-Methyl-3-ethyl-4-hydroxy-4-( p-acctoxyphenyl)cyclohexanecarboxylate A. 2.5 g. of methyl2-methyl-3-ethyl-4-hydroxy-4-(phydroxyphenyl )cyclohexanccarhoxylate(Example Vll') is acetylated for 20 minutes at 25C. in a mixture of ml.of pyridine plus 15 ml. of acetic anhydride. Hydrolysis of theacetylation solution in ice and water affords a viscous oily productwhich becomes crystalline on maintaining the hydrolysis mixture at 0C.for

20 hours. This solid is filtered off with suction and is driedthoroughly in air and is recrystallized from ether to afford methyl2-methyl-3-ethyl-4-hydroxy-4-(pacetoxyphenyl)cyclohexanecarboxylate,white prisms which melt at l l8l 19C.

Anal: Calcd. for C H O C, C, 68.31; H, 7.80.

Akmax. (KBr): 2.87, 5.71, 5.82, 8.10-8.30, 8.65, 9.61, 9.80, 10.91,ll.80 u..

B. The anhydride of 2-methyl-3-ethyl-4-hydroxy-4-(p-acetoxyphenyl)cyclohexanccarboxylic acid (Example V) is boiled underreflux in pyridine plus methanol for 30 minutes to yield a mixture ofproducts from which there is isolated methyl 2-methyl-3-ethyl-4-hydroxy-4( p-acetoxyphenyl )cyclohexanecarboxylate m.p. ll8-ll9C.

Other products are2-methyl-3-ethyl-4-hydroxy-4-(pacetoxyphenyl)cyclohexanecarboxylic acid(Example IV) and2-methyl-3-ethyl-4-hydroxy-4-(phydroxyphenyl)cyclohexanecarboxylic acid(Example 111).

68.24; H, 7.84. Found:

EXAMPLE IX 2-Methyl-3-ethyl-4-( p-hydroxyphenyl )4-cyclohexenecarboxylic Acid A. To a vigorously stirred suspension of 6.0g. of 2- methyl-3-ethyl-4-hydroxy4-(p-hydroxyphenyl)cyclohexanecarboxylic acid (Example 111) in 100 ml.of ether is added 4.0 ml. of boron trifluoride etherate. After 4 minutesof stirring at 25C., the solid has com pletely dissolved and at thispoint g. of ice plus 'water is added. Vigorous shaking destroys thecatalyst and the layers are separated. The ether solution is washedtwice more with small portions of water and is dried with anhydrousmagnesium sulfate and evaporated under vacuum to a glassy residue. Theresidue is dissolved in 45 ml. of warm methylene dichloride, and a fewdrops of water are added. The mixture is stirred for several hours at25C. to afford 3.4 g. of fine anhydrous granules of2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4- cyclohexenecarboxylic acid whichmelts at l93-195C. A second recrystallization affords material of m.p.l97-199C.

The infrared spectrum, in a potassium bromide wafer, is unusual for thisstructure. Apparently, this material exists as a crystal lattice dimeras crystallized from methylene chloride in the presence of water. 1t maybe sublimed under vacuum without chemical change, but the sublimate isobserved to be an amorphous glass which, upon heating, is transformed tothe crystalline form which melts at l97l99C. and which exhibits theinfrared spectral properties noted below. roton magnetic resonance showsone vinyl hydrogen.

Recrystallization from nitromethane gives a different allotropic formwith a somewhat altered infrared spectrum. However, this is converted(upon heating) to the form described.

Anal: Calcd. for C ,H- ,,,O;,: C, 73.82; H, 7.74. Found: C, 73.87; H,7.87.

Akmax. (KBr): From CH CI H O: 3.00, 5.88, 8.1 l. 8.75, .79, 12.08,14.20, l4.90p.. From CH NO 2.95, 5.88, 8.10, 8.50, 11.60-11.70, 1380p.

Acetylation of this A -acid with acetic anhydride in the presence of alarge amount of pyridine affords a high yield of2mcthyl-3-cthyl-4-(p-acctoxyphenyl)-4- cyclohexenecarboxylic acid.identical with that obtained in Example Xlll.

' vll B. A mixture of 0.4 g. of '2-methyl-3-ethyl-4'-(pacetoxyphenyl)-4-cyclohexenecarboxylic' acid (Example Xlll), 1.2 g. of'potassiumbicarbonate and 25 ml. of

water is stirred and boiled under reflux for 10-minutes. After cooling,the bicarbonate solution is acidified with dilute hydrochloric acid andis extracted with two'20 ml. portions of ether. The combined ethersolution is dried with anhydrous magnesium sulfate and is evaporatedunder vacuum to a glassy residue which is recrystallized twice frommethylene dichloride in the presence of water, as described in A, toafford 0.25 g. of finewhite granules which melt at 194197C. and whichare spectrally identical with the A-acid described in A. 1

C. A mixture of 3.0 g. ofthe anhydride of 2-methyl-3-ethyl-4-hydroxy-4-( p-acetoxyphenyl )cyclohexanecar boxylic acid(Example V), 0.6 g. of p-toluenesulfonic acid monohydrate, 7.0 ml. ofacetic anhydride and 100 ml. of acetic acid is boiled under reflux for10 minutes hours. The hydrolysis mixture is filtered to clarify and.

it is then acidified with dilute hydrochloric acid and extracted twicewith ether. Crystallization of the glassy ether residue in the mannerdescribed in A affords 1.2 g. I of2-methyl-3-ethyl-4-(p-hydroxyphenyl)r4- cyclohexenecarboxylic acid,identical with the material described in A and B.

D. A solution of 0.1 g. of the C-lactone of 2-methyl-3-ethyl-4-hydroxy-4-( p-hydroxyphenyl )cyclohexanecarboxylic acid(Example XV) and 0.2 g. of sodium hydroxide in 2 ml. of water and 2 ml.of methanol is boiled under reflux for 75 minutes. Ten ml. of water isadded to .the alkaline solution and it is evaporated to a volume of 8ml. to remove methanol and it is then. cooled and acidified with dilutehydrochloric acid. .The oil thus precipitated is extracted with ether.Drying and evaporation of the other solution affords a glassy residuewhich is dissolved in ml. of nitromethane' andireevaporated to removeall traces of ether. The oil is now redissolved in 5 ml. of nitromethaneand stored at 0C. to afford 0.03 g. of white microprisms of 2-methyl3-ethyl-44 p-hydroxyphenyl )-4-cyclohexenecarboxylic acid which has aninfrared spectrum (KBr) identical with the material described in A, ascrystallized from nitromethane.

EXAMPLE X Sodium Salt of 2-methyl-3-ethyl-4-( p-hydroxyphenyl )-4--cyclohexenecarboxylic Acid To a solution of 0.5 g. of2-methyl-3-ethyl-4-(phydroxyphenyl)-4-cyclohexenecarboxylic acid(Example 1X) in 12 m1. of methanol is added 0.2 g. of sodium bicarbonateand 20 ml. of water. The mixture is stirred at 45C. for minutes and isconcentrated under vac uum to a solid residue. The latter is thoroughlymixed with 15 ml. of methanol and the mixture is filtered to remove asmall amount of sodium. bicarbonate. The

to afford the sodium salt of2-methyl-3-ethyl-4-(phydroxyphenyl)-4-cyclohexenecarboxylic acid as afluffy, white, non-hygroscopic powder which readily dissolves in water.

)dtmax. (KBr): 2.92, 6.45, 6.60, 7.07, 7.95, 8.08, 8.50, 9.08, 12.02;.t.

EXAMPLE X1 2-Methyl-3-ethyl-4-( p-hydroxyphenyl )-3-cyclohexenecarboxylic Acid A. A mixture of 2.0 g. ofZ-methyl-3-ethyl-4-hydroxy- 4-(p-hydroxyphenyl)cyclohexanecarboxylicacid (Example lll), 0.6 g. of p-toluenesulfonic acid monohydrateand100ml. of acetic acid is boiled under reflux for 40 'minutes and thesolution is evaporated under vacuum to a glassy residue. The latter isdissolved in 70 ml. of 4% aqueous sodium hydroxide and this solution isneutralized by bubbling through it a vigorous stream of carbon dioxideuntil it reacts neutral to test paper. Extraction of this neutralaqueous solution with two small portions of methylene dichloride removes0.3 g.

of lactonic material which is purified in the manner described inExample XVI.

The aqueous solution is acidified with dilute hydrochloric acid and isextracted with three 20 ml. portions of methylene dichloride. Thecombined extracts are dried with anhydrous magnesium sulfate andevaporated under vacuum to an amorphous glass. The latter is redissolvedin 15 ml. of methylene dichloride and stored at 0C. to afford 0.8 g. of2-methyl-3-ethyl-4-(phydroxyphenyl )-3-cyclohexenecarboxylic acid aswhite microprisms. This material apparently exists in severalpolymorphic forms depending upon the speed and mode of crystallization.Very slow crystallization from methylene dichloride in the presence of afew drops of water affords fine anhydrous prisms which melt at 147-148C.Proton magnetic resonance shows to vinyl hydrogen. 7

Anal: Calcd. for C H O C, 73.82; H, 7.74. Found:

AAmax. (KBr): 2.92, 5.88, 8.08, 8.51, 8.71, 9.04,

B. A mixture of 0.8 g. of2-methyl-3-ethyl-4-(pacetoxyphenyl)-3-cyclohexenecarboxylic acid(Example Xll), 3.0 g. of potassium bicarbonate and 60 ml. of water isstirred and boiled under reflux for 10 minutes.

. After cooling, the bicarbonate solution is acidified with clearfiltrate is evaporated to dryness and the solid residue is pulverizedand dried over phosphoric anhydride dilute hydrochloric acid and isextracted with two 40 ml. po rtions of ether. The combined ethersolution is dried with anhydrous magnesium sulfate and is evaporatedunder vacuum to a glassy residue which is recrystallized from methylenedichloride in the presence of water, as described in A, to afford 0.6 g.of white microprisms which melt at l45-147C., and which are spectrallyidentical with the A"-acid as isolated in A.

EXAMPLE Xll Sodium Salt of 2-methyl-3 -ethyl-4-( p-hydroxyphenyl)-3-cyclohexenecarboxylic Acid Following the procedure of Example X,0.35 g. of 2 methyl3-ethyl.-4-( p-hydroxyphenyl )-3-cyclohexenecarboxylic acid (Example X1) is neutralized in aqueousmethanolwith 0.15 g. of sodium bicar bonate. Identical working-upaffords the sodium salt of 13 the carboxylic acid as a fluffy, white,non'hygroscopic powder which readily dissolves in water.

AAmax. (KBr): 2.92. 6.45. 6.60, 7.07, 7.95, 8.08, 8.52, 8.75, 9.09,11.32, 12.04;/..

EXAMPLE xm 2-Methyl3-ethyl-4-( p-acetoxyphcnyl )-4-cyclohexenecarboxylic Acid A mixture of 3.9 g. of2-methyl-3-ethyl-4-hydroxy-4- (p-acetoxyphenyl)cyclohexanecarboxylicacid (Example IV) and 200 ml. of acetic acid is rapidly brought to theboil and 1.0 g. of p-toluenesulfonic acid monohydrate is added in oneportion. After a -minute period of boiling under reflux, the acetic acidsolution is treated with 2.0 g. of sodium acetate to neutralize thetoluenesulfonic acid. The mixture is evaporated under vacuum to removeacetic acid and the pasty residue is shaken with 200 ml. of ether and 50ml. of water. The ether layer is dried with anhydrous magnesium sulfateand concentrated under vacuum to a tacky crystalline residue. The latteris recrystallized twice from ether plus hexane to afford 2.1 g. of2-methyl-3-cthyl-4-(pacetoxyphcnyl)-4-cyclohcxenecarboxylic acid, whiteprisms which melt at l54-155C. Proton magnetic resonance shows one vinylproton in this compound.

Anal: Calcd. for C,,,H O C, 71.50; H, 7.33. Found: C. 71.25; H, 7.58.

AAmax. (KBr): 5.69, 5.91, 8.l9, 8.30, 9.75, 10.90, 11.73, 11.90 1"EXAMPLE XlV 2Methyl-3ethyl4-( p-acetoxyphenyl )3- cyclohexenecarboxylicAcid A mixture of 1.0 g. of 2-mcthyl-3-ethyl-4-hydroxy-4(p-hydroxyphenyl)cyclohexanecarboxylic acid (Example III), 0.3 g. ofp-toluenesulfonic acid and 50 ml. of acetic acid is boiled under refluxfor 30 minutes and is evaporated under vacuum to remove acetic acid. Theglassy residue is dissolved in ml. of pyridine and 3 ml. of aceticanhydride is added. After it has been kept at C. for 20 minutes, theacetylation mixture is hydrolyzed in ice water and the oily product isextracted with two 50 ml. portions of ether. The combined ether solutionis chilled to 0C. and is quickly extracted with two ice-cold 40 ml.portions of 79? aqueous potassium carbonate to separate carboxylic acidfrom the byproduct lactone which is also formed on dehydration. Thepotassium carbonate extracts are immediately acidified with cold dilutehydrochloric acid and then extracted with two 35 ml. portions of ether.The combined ether solution is washed twice with water, dried withanhydrous magnesium sulfate and evaporated under vacuum to a crystallineresidue which is recrystallizcd twice from other plus hexane to afford0.65 g. of 2-methyl-3-ethyl-4-(p-acetoxyphenyl )-3-cyclohexenecarboxylic acid, white prisms which melt at l45l47C. Protonmagnetic resonance shows no vinyl hydrogen.

Anal: Calcd. for C,,,H- O C, 71.50; H, 7.33. Found: C, 71.66; H. 7.29.

Ahmax. (KBr): 5.69, 5.88, 8.22, 8.37, 9.74. 9.85, 10.92, 11.41, 1117 B.Example lX-C describes the dehydration of 3.0 g. of the anhydride of2-methyl-3-ethyl-4-hydroxy-(pacetoxyphcnyl)cyclohexanecarboxylic acidand the subsequent isolation of 2-methyl-3-ethyl-4-(phydroxyphenyl)-4-cyclohexenecarboxylic acid.

The methylene dichloride mother liquor from recrystallization of thelatter is evaporated to a glassy residue which is then boiled underreflux for 30 minutes in 50 ml. of acetic acid containing 0.3 g. ofp-toluencsulfonic acid monohydrate. The acetic acid solution isevaporated under vacuum to a viscous oil which is dissolved in 20 ml. ofpyridine containing 3 ml. of acetic anhydride. After it has been held at25C. for 20 minutes, the acetylation mixture is hydrolyzed in ice andwater and the oily product is extracted with ether. Washing of the ethersolution with cold dilute hydrochloric acid removes pyridine, and theacidic reaction products are extracted by washing twice with cold 7%potassium carbonate solutions. The ether solution, which contains onlylactones, is reserved for use in Example XVllI. The combined carbonatewashes are immediately acidified with hydrochloric acid and the oilycarboxylic acid is extracted with ether. The residue from evaporation ofthis ether solution is recrystallized from etherhexane to afford 0.65 g.of 2-methyl-3ethyl-4-(pacetoxyphenyl)-3-cyclohexeneearboxylic acid,cream prisms which melt at l40l45C., whose infrared spectrum isidentical with that of the material described in A.

EXAMPLE XV C-Lactone of2-Methyl-3-ethyl4'hydroxy4-(p-hydroxyphenyl)cyclohexanecarboxylic Acid,and C-Lactone of2-Methyl3-ethyl-4-hydroxy-4-(p-acetoxyphenyl)cyclohexanecarboxylic AcidA. A mixture of 0.3 g. of crystalline C-lactone of 2-methyl3-ethyl-4-hydroxy-4-( ptetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid (Example I), 7 ml. of methanol and 1 ml. ofwater containing two drops of 12.5 N. hydrochloric acid is stirred at25C. for 15 minutes. The resulting clear solution is diluted with ml. ofwater and extracted with two 25 ml. portions of ether. The combinedether solution is washed with water and 5% aqueous sodium bicarbonateand is dried with anhydrous magnesium sulfate and evaporated undervacuum to a pasty solid residue. The latter is recrystallized from etherplus hexane to afford 0.2 g. of the C-lactone of 2methyl-3-ethyl-4-hydroxy-4-(p-hydroxyphenyl)cyclohexanecarboxylic acid as fine whitegranules which melt at l58l59C.

Analz Calcd. for C H O C, 73.82; H, 7.74. Found: C, 73.89; H, 7.93.

Mtmax. (KBr): 2.95, 5.80, 7.88, 8.18, 9.1 l, 9.85, 1 199 1..

B. Acetylation of 0.1 g. of the hydroxyphenyl lactone described in Awith acetic anhydride in pyridine for twenty minutes at 25C., followedby conventional hydrolysis and workup of the reaction mixture affords0.1 g. of the corresponding acetoxyphcnyl C'lactone as a viscous oilhaving a boiling point of l55-l60C. at 0.01 mm. and an index ofrefraction 11,, 1.5369.

Anal: Calcd. for C M- 0,: C, 71.50; H, 7.33. Found: C, 70.98; H, 7.37.

Mtmax. (Neat): 5.70, 5.18-5.36, 9.13. 9.85. 10.94, 1 1.78 2.

EXAMPLE XVI Lactone of 2-Methyl-3-cthyl-4 hydroxy-4 -hydroxyphenyl)cyclohexanecarboxylic Acid, and B-Lactone of2-Methyl-3-cthyl-4-hydroxy-4( p-aeetoxyphenyl )cyclohexanecarboxylicAcid A. The 0.3 g. portion of lactonic material described as aby-product in Example X1 had been obtained as a crystalline residue frommethylene dichloride extraction of an aqueous bicarbonate solution ofproducts from strong acid dehydration of 2-methyl-3-ethyl-4- hydroxy-4-(p-hydroxyphenyl )cyclohexanecarboxylic acid. This 0.3 g. of lactone isrecrystallized from ether to afford 0.2 g. of white prisms which melt atl84185C. According to its infrared spectrum, it is of a differentstereochemical series from the C-lactone (Example XV) and it is nowdesignated a B-laetone of 2-methyl- 3 -ethyl-4-hydroxy-4-(p-hydroxyphenyl )cyclohexanecarboxylic acid.

Anal: Calcd. for C H O C, 73.82; H, 7.74. Found: C, 73.88; H, 7.86.

Mtmax. (KBr): 2.94, 5.69, 7.94, 8.73, 9.00, 10.70, 11.99;!"

B. Acetylation of 0.1 g. of the hydroxyphenyl lactone described in Awith acetic anhydride in pyridine for 20 minutes at 25C., followed byconventional hydrolysis and workup of the reaction mixture affords 0.1g. of a solid acetoxyphenyl B-lactone which is recrystallized from etherto afford white prisms which melt at 151152C. Anal: Calcd. for C H O C,71.50; H, 7.33. Found: C, 71.68; H, 7.27.

Akmax. (KBr): 5.61, 8.20, 8.32, 8.39, 8.79, 10.71, 10.82, 10.95p..

EXAMPLE XVlI A-Lactone of 2-Methyl-3-ethyl-4-hydroxy-4-( p-hydroxyphenyl)cyclohexanecarboxylic Acid, and A-Lactone of2-Methyl-3-ethyl-4-hydroxy-4(p-acetoxyphenyl )eyclohexanecarboxylic AcidA. The methylene dichloride-soluble material of Example 11, obtained as22 g. of viscous oil after crystallization of the hydroxy acid, isdepyranylated by dis solving it in 500 ml. of methanol and 40 ml. ofwater containing 4 ml. of 12.5 N. hydrochloric acid. After this solutionhas been maintained at 25C. for 1 hour, it is diluted with 500 ml. ofwater and is evaporated under vacuum to a volume of 350 ml. to removemethanol. To the residual mixture of viscous oil and water is added 60ml. of 25% aqueous sodium hydroxide and the resulting clear solution isneutralized by bubbling through it a vigorous stream of carbon dioxideuntil it reacts neutral to test paper. The precipitate material, a crudelactone, is extracted with 100 ml. of methylene dichloride and thisextract is dried with anhydrous magnesium sulfate and evaporated to atacky crystalline residue. The latter is recrystallized from ether toafford 2.5 g. of white prisms which melt at 169170C. According to itsinfrared spectrum, this is a lactone of a different stereoehemicalseries from the C-lactone (Example XV) and the B-lactone (Example XVI).lt is now designated an A-lactone of 2-methyl-3-ethyl4- hydroxy-4-(p-hydroxyphenyl )cyclohexanecarboxylic acid.

Anal: Calcd. for C M- C, 73.82; H, 7.74. Found: C, 73.89; H, 7.93.

ham-ax. (KBr); 2.94, 5.83, 8.12, 8.32, 8.76, 9.92, 10.42, 11.68, 11.93,.

B. Acetylation of 1.0 g. of the hydroxyphenyl lactone described in Awith acetic anhydride in pyridine for 30 minutes at 25C., followed byconventional hydrolysis and workup of the reaction affords 1.0 g. of asolid acetoxyphenyl A-lactone which is recrystallized from ether plushexane to afford white prisms which melt at 7475C.

Anal: Calcd. for C ,,H O C, 71.50; H, 7.33. Found: C, 71.44; H, 7.24.

Mtmax. (KBr): 5.64, 5.71, 8.20-8.32, 9.03, 9.88, 10.91, 1l.74p..

EXAMPLE XVlll D-Lactone of 2-Methyl-3-ethyl-4-hydroxy-4-(p-acetoxyphenyl )cyclohexanecarboxylic Acid A. The ether solution ofExample XIV-B which has been described as containing lactones, isevaporated to afford 0.45 g. of a crystalline mixture of lactones. Thisis fractionally crystallized between ether and methanol, whereby thereis finally obtained 0.15 g. of the B- lactone, which has infrared andproton magnetic resonance spectra identical with those of the materialdescribed in Example XVI-B. There is also obtained 0.04 g. of anotherlactone, different from the A, B, and C- lactones (Examples XV-B, XVl-B,and XVII-B) in its infrared and proton magnetic resonance spectra. Thislactone melts at 154155C., and is called the D lactone of2-methyl-3-ethyl-4-hydroxy4( pacetoxyphenyl )cyclohexanecarboxylic acid.

Anal: Calcd. for C ,,H O C, 71.50; H, 7.33. Found: C, 72.22; H, 7.50.

Akmax. (KBr): 5.71, 8.27, 8.38, 9.87, 10.71, 10.97. 1l.73 .1..

EXAMPLE XlX Methyl 2-Methyl-3-ethyl-4-( p-hydroxyphenyl )-4-cyclohexenecarboxylate To a solution of 3.0 g. of methyl2-methyl-3-ethyl-4- hydroxy-4-(p-hydroxyphenyl)cyclohexanecarboxylate(Example V11) in 75 ml. of ether is added 3 ml. 01 boron trifluorideetherate. The reaction mixture is maintained at 23C. for 5 minutes andthen is shaker with 20 m1. of ice and water. The ether layer is washecwith aqueous sodium bicarbonate and is dried with an- 2 hydrousmagnesium sulfate and evaporated under vac EXAMPLE XX Methyl2-Methyl-3-ethyl-4-( p-hydroxyphenyl )-3- cyclohexenecarboxylate Amixture of 3.5 g. of methyl 2-methyl-3-ethyl-4- hydroxy( p-hydroxyphenyl)cyclohexanecarboxylate (Example V11) and 0.9 g. of p-toluenesulfonicacid monohydrate in 150 ml. of acetic acid is boiled under reflux for 25minutes and then the resulting solution is concentrated under vacuum toa viscous brown oil. The latter is dissolved in 150 ml. of ether and thesolution is washed twice with aqueous potassium bicarbonate and thendried with magnesium sulfate and evaporated to a yellow oil.Distillation of this affords 3.0 g. of a viscous oil which boils at140150C. at 0.002 mm. This is dissolved in 12 ml. of nitromethane andstored at C. to cause crystallization of 1.6 g. of dense clusters ofprisms, which upon further recrystallization from nitromethane affords1.5 g. of methyl 2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenecarboxylate, large white prisms whichmelt at l 131 14C.

Proton magnetic resonance is not diagnostic for the absence of a vinylproton in this phenolic ester because the phenol proton absorbs in thevinyl region. However, acetylation with acetic anhydride and pyridinegives an oily acetoxyphenyl methyl ester which shows no vinyl proton.thus substantiating the assignment of unsaturation to the 3-4 positionsof the alicyclic portion of the molecule.

Anal: Calcd. for C H O C, 74.42; H, 8.08. Found: C 74.20; H, 8.16.

AAmax. (KBr): 2.98, 5.88, 7.89, 8.07, 8.12, 8.53, 9.87, 11.83, 12.11;.t.

While the invention has been described and exemplified with respect tothe preparation of compounds wherein the cyclohexane and cyclohexeneportion of the structure have 2-methyl-3-ethyl substitution, and whereinthe phenyl portion of the structure has either p-hydroxy or p-acetoxysubstitution, it will be apparent to one skilled in the art that othersubstitutions are readily available.

By selecting as one of the starting materials for use in Example 1, anappropriate material such as: ethyl2,3-dimethyl-4-ketocyclohexanecarboxylate, ethyl2,3-diethyl-4-ketocyclohexanecarboxylate, ethyl2.3-dipropyl4-ketocyclohcxanecarboxylate, ethyl2-ethyl-3-methyl'4-ketocyclohexanecarboxylate,

ethyl 2-methyl-3-propyl-4-ketocyclohexanecarboxylate.

ethyl 2-ethyl-3propyl-4-ketocyclohexanecarboxylate,

etc.,

the 2 and 3 positions of the cyclohexyl portion of the structure may besubstituted withan alkyl of from one to eight carbon atoms.

The phenyl portion of the structure may be parasubstituted with an esterof from two to nine carbon atoms by esterifying the substituted(p-hydroxyphenyl)cyclohexane carboxylic acid or carboxylate with anappropriate acid anhydridesuch as propionic anhydride, normal andisobutyric anhydride, caprylic anhydride, etc.

As noted earlier, the compounds of formulae 2, 3 and 4 are effective inthe suppression of reproduction in female animals. In testing thecompounds for antilittering activity, an experimental group of animalssuch as rats, rabbits, or mice, for example, is fed a basic dietcontaining the compound to be tested for a period of 7 days. For thepurpose of illustration, adult rats will be employed as the testanimals. After receiving the basic diet, the rats are then cohabitatedat a ratio of two males to five females and allowed to copulate freelyfor a period of 15 days during which time they are fed the basic dietcontaining the test compound. The sexes are then segregated and thebasic diet only continued. A control group of animals is treatedidentically except that the basic diet does not contain the compound tobe tested. The females are observed for littering for a 21-day periodfollowing the period of cohabitation.

The minimum daily dose required to prevent littering in the test animalsfor various compounds tested is tabulated below:

TABLE I Antilittering Activity (oral) Compound (dose wgt./kg.; Rat)2-methyl-3-ethyl-4- (I) 5 mg. hydrox y-4-( p-tetra hydropyranyloxyphenylcyclohexanecarboxylic acid (Example 11. p. 8)2-methyl-3-ethyl-4-hydroxy- 4-(p-hydroxyphenyl) cyclohexanecarboxylicacid (Example 111, p. 10) 2-methyl-3-ethyl-4-hydroxy- 4-(p-acetoxyphenyl) cyclohcxanecarboxylic acid (Example IV, p. l l)2-methyl-3-ethyl-4- (p-hydroxyphenyl )-4- cyclohexcnecarboxylic acid(Example 1X. p. 15) 2-methyl-3-cthyl-4- (phydroxyphenyl )3-cyclohexcnecarboxylic acid (Example Xl. p. 18-20) 2-methyl'3-ethyl-4-(p-acetoxyphenyl )-4- eyelohexcnecarboxylic acid (Example Xlll, p.20-21) methyl 2-methyl3-ethyl-4- (p-hydroxyphcnyl )-4-cyclohcxenecarhoxylatc (Example XIX. p. 27) methyl 2-methyl-3-ethyl-4-(p-hydroxyphenyl )-3- cyclohexenecarboxylatc (Example XX, p. 27-28)(5000 fig.)

(mas mg. (2500 pg.)

10 mg. (1000 pg.)

1.0 mg. 1000 ,t

0.005 mg. (5 pg.)

0.001 mg. 1 .Lg.)

0005 mg. (5 ,ug.)

0,010 mg. (10 #g.)

0.001 mg. 1 ug.)

The data in the following table demonstrate the antilittering effect inrats of various compounds:

c clohexcnecurhoxylic acid Control TABLE ll Cntinued Compound Thepost-coital activity of the compounds was determined using adult ratsand rabbits as the test animals. Adult Wistar rats and New Zealandrabbits were used in the test. Rats exhibiting sperm on the morning ofestrus were used in the test. Receptive does were allowed a singlemating with each of two bucks and were used was used to evaporate theether and appropriate dilutions made with sesame oil for each testgroup. ,Rats were sacrificed on day 9 of pregnancy and examined forimplants. Rabbits were examined for implants on day 20 of pregnancy. Theresults are shown in Tables [[1 and IV.

TABLE [II No. Dose Day(s) of PregJ Total No. Comments Rats Compoundg/kg) Pregnancy Treated Total Implants Control 0 .2 5/5 69 All normal 52methyl-3-ethyl-4 5 [.2 2/5 l()( 1.9) All resorb- (p-hydroxyphenyl )-3-I ing cyclohexeneearboxylic acid 5 2-methyl-3-ethyl-4- L2 2/5 2Resorbing (p-hydroxyphcnyl )-4 cyclohcxenecarhoxylic acid TABLE IV No.Dose Day(s) of Preg./ Number of Implants Rabbits Compound pg/kg)Pregnancy Treated Total Total Normal Resorbing 5 Control 0 0-3 5/5 36 324 9 2-mcthyI-3-ethyl 4 100 0-3 0/5 0 0 0 (p-hydroxyphenyl )-3eyclohexcnccarboxylic acid 5 2-methyl-3-ethyl-4- I00 0-3 I /5 l 0 l(p-hydroxypnenyl )-4 cyclohcxeneearhoxylic acid in the test. Thecompounds were administered orally by means of a stomach tube needle onthe morning of sperm and the following day to rats, and on the day ofmating and the following 3 days to rabbits. Each compound was preparedby first dissolving it in ether, followed by the addition of sesame oil.Gentle warm air OH 0 R0 l I v RI I l o u n ti-littering amount of acompound selected from the group consisting of:

and

Rlllo wherein R is selected from the group consisting of hydrogen, loweracyl of from two to nine carbon atoms and tetrahydropyranyl, R isselected from the group consisting of hydrogen and lower alkyl of fromone to eight carbon atoms, R" is lower alkyl of from one to eight carbonatoms, and R is selected from the group consisting of hydrogen and loweracyl of from two to nine carbon atoms, or alkali metal salts thereof.

2. The method of claim I in which the compound isZ-methyl-3-ethyI-4-hydroxy-4-(p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid.

3. The method of claim 1 in which the compound is methylZ-methyl-3-ethyl-4-hydroxy-4-( p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylate.

4. The method of claim 1 in which the compound is2-methyl-3-ethyl-4-hydroxy-4-(p-hydroxyphenyl) cyclohexanecarboxylicacid or the alkali metal salt thereof.

5. The method of claim I in which the compound isZ-methyl-3-ethyl-4-hydroxy-4-( p-acetoxyphenyl) cyclohexanecarboxylicacid or the alkali metal salt thereof.

6. The method of claim 1 in which the compound is methyl2-methyl-3-ethyl-4-hydroxy-4-(phydroxyphenyl )cyclohexanecarboxylate.

7. The method of claim 1 in which the compound is methyl2-methyl-3-ethyl-4-hydroxy-4-( paeetoxyphe nyl )cyclohexanecarboxylate.

8. The method of claim 1 in which the compound is 2-methyl-3-ethyl-4-(p-hydroxyphenyl )-4- cyclohexenecarboxylic acid or the alkali metal saltthereof.

9. The method of claim 1 in which the compound is2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3- cyclohexenecarboxylic acid orthe alkali metal salt thereof.

10. The method of claim 1 in which the compound is 2-methyl-3-ethyl-4-(p-acetoxyphenyl )-4- cyclohexenecarboxylic acid or the alkali metal saltthereof.

11. The method of claim 1 in which the compound is 2-methyl-3-ethyl-4-(p-acetoxyphenyl )-3' cyclohexenecarboxylic acid or the alkali metal saltthereof.

12. The method of claim 1 in which the compound is methyl2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4- cyclohexcnecarboxylate.

13. The method of claim 1 in which the compound is methyl2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3- cyclohexenecarboxylate.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 3,903,292

DATED September 2,1975 INVENTOR(5) 3 George Karmas It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

[SEAL] In Column 5, line 61, "while a soluticn of 58 ethyl" should readwhile a solution of 58 g. ethy In Column 15,1ine 2, "Lactone of2-Methyl-3-ethylr should read B-Lactone of 2-Methyl-3-ethylr In Column15,1ine 5h, "The precipitate material" should read The precipitatedmaterial In Column 16, line 51, "and then is shaker" should read andthen is shaken In Column 16, line 58, "affords 1.53.0" should readaffords 1.5 g. of

In Column 16, line 61,"?hich melt a" should read which melt at Signedand Sealed this A ttest:

RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner uflarenrsand Trademarks

1. A METHOD OF SUPPRESSING REPRODUCTION COMPRISING ADMINISERING ORALLYTO A FEMALE ANIMAL AN EFFECTIVE ANTI-LITTERING AMOUNT OF A COMPOUNDSELECTED FROM THE GROUP CONSISTING OF1-(HO-),1-(4-(R-O-)PHENYL),2,3-DI(R"-),4-(R''-OOC-)CYCLOHEXANE,
 2. Themethod of claim 1 in which the compound is2-methyl-3-ethyl-4-hydroxy-4-(p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylic acid.
 3. The method of claim 1 in which thecompound is methyl2-methyl-3-ethyl-4-hydroxy-4-(p-tetrahydropyranyloxyphenyl)cyclohexanecarboxylate.
 4. The method of claim 1 in which the compoundis 2-methyl-3-ethyl-4-hydroxy-4-(p-hydroxyphenyl) cyclohexanecarboxylicacid or the alkali metal salt thereof.
 5. The method of claim 1 in whichthe compound is 2-methyl-3-ethyl-4-hydroxy-4-(p-acetoxyphenyl)cyclohexanecarboxylic acid or the alkali metal salt thereof.
 6. Themethod of claim 1 in which the compound is methyl2-methyl-3-ethyl-4-hydroxy-4-(p-hydroxyphenyl)cyclohexanecarboxylate. 7.The method of claim 1 in which the compound is methyl2-methyl-3-ethyl-4-hydroxy-4-(p-acetoxyphenyl)cyclohexanecarboxylate. 8.The method of claim 1 in which the compound is2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenecarboxylic acid or thealkali metal salt thereof.
 9. The method of claim 1 in which thecompound is 2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenecarboxylicacid or the alkali metal salt thereof.
 10. The method of claim 1 inwhich the compound is2-methyl-3-ethyl-4-(p-acetoxyphenyl)-4-cyclohexenecarboxylic acid or thealkali metal salt thereof.
 11. The method of claim 1 in which thecompound is 2-methyl-3-ethyl-4-(p-acetoxyphenyl)-3-cyclohexenecarboxylicacid or the alkali metal salt thereof.
 12. The method of claim 1 inwhich the compound is methyl2-methyl-3-ethyl-4-(p-hydroxyphenyl)-4-cyclohexenecarboxylate.
 13. Themethod of claim 1 in which the compound is methyl2-methyl-3-ethyl-4-(p-hydroxyphenyl)-3-cyclohexenecarboxylate.